Model organisms and translational research

There are two common definitions. Birney leans toward defining a model organism as one that models human biochemistry and physiology. This is a common definition. It emphasizes the meaning of "model" as "model of something."

The other definition is more like the meaning of model as "ideal" or "useful" as in Cromwell's New Model Army. The two definitions are not mutually exclusive but it's important to recognize the biases when you hear scientists talk about model organisms.

One of the first model organisms was the fruit fly, Drosophila melanogaster. It was easy to culture and had relatively short generation times. As more and more scientists began work on Drosophila genetics, it became a very useful tool for probing all kinds of biological questions. Back in the 1930s, nobody really thought of fruit flies as good models for the study of human diseases.

Later on (1940s), the phage group developed bacteria and bacteriophage as model organisms. They were used to study genetics and basic biological processes. They were convenient because so many different groups were working on the same systems and their knowledge could be readily shared. This is why we know so much about Escherichia coli—an otherwise unremarkable species.

Arabidopsis thaliana is another model organism. Many discussions about model organisms don't mention it. Nor do they mention Daphnia or Neurospora. That's usually because they are going with the first definition of model organism and they don't see these examples as being particularly relevant.

Ewan Birney's point is that more and more health research is directly involved in studying humans and human cell lines. According to him, there's still a place for studying some "model" organisms because we need to understand basic biological processes. In other words, some basic research is necessary in order to understand human medicine. That's why he's "defending" model organisms.

Translational research

Strictly speaking, translational research is research that's directed toward some useful goal or product. These days it's almost always used in the context of research that could prove useful in human medicine.

Ewan Birnely supports translation research and he's upset that there seems to be a conflict between basic science and translational research.

Crude arguments that play “translation” and “basic research”, or “human disease” and “fundamental discoveries” off each other are depressing. The idea that humans are the only model organism for the future is simply misguided mischief, and opens up the dangerous possibility that people might actually start to believe it – and it’s just as frustrating to hear some people claim that one can only do translational, healthcare related science in humans, and no profound basic discoveries will emerge from human investigation. Taking an extreme position to make either point is annoying, but it belies an underlying tension that needs to be resolved. I think these arguments are more about conflict between of tribes of scientists who are now interacting more and more. There is also an element of jockeying for position, both as individuals and as tribes. We need to get beyond this.

A ‘balanced portfolio’ sounds great, but there is no straightforward recipe for compiling one. What does the best ‘balanced portfolio’ of research look like? How much “pure” disease focus on humans, and what else to add? A tablespoon of yeast, a teaspoon of serendipity and a dash of electric eel? What part of that portfolio would a particular funding agency, charity, institute or scheme take on? How to assess a slew of wildly different proposals, each with different rationales?

There are no easy answers to these questions, but we do need to realise that the lines between ‘basic’ and ‘translational’ research are now fully blurred – both are essential parts of the same process of understanding life, with massive spill-over effects across many practical aspects of our world, our health above all.

My view is somewhat different. I think there really is a difference between someone who is studying speciation in Drosophila or the mechanism of photosynthesis and someone who is mostly interested in curing cystic fibrosis.

I think there's a huge difference between basic research and translational research. This does not mean that some of the discoveries of basic researchers will never be relevant to health and disease, of course they will, but that doesn't mean that the "lines are fully blurred." There's still a lot of fundamental basic research addressing questions that have nothing to do with health and disease and will never be relevant.

I don't think we should fall into the trap of justifying fundamental curiosity-motivated research soley on the basis of what it might contribute to the "really important" stuff like translational research. We should be supporting basic research because it contributes to knowledge and not necessarily to health and disease.

8 comments
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Years ago when I was a grad student in a Drosophila lab people I met in day to day situations would invariably get around to telling me about some pain they were having somewhere in their body and ask for medical advice. Eventually I got tired of telling them that being in the life sciences didn't mean I had any medical expertise so I started to give medical advice. Whatever complaint they had I'd suggest it was a mite infestation and then mention that whenever our fly cultures were sick it was usually due to a mite infestation. For some reason Larry's musings above reminded me of this.

I totally agree. We need to try to learn what diversity of organisms exist, how they all function, and how they all got here. We need to do this mainly because of our wish to know. Incidentally, we will learn unexpected things that will help us deal with human health, or food plants and animals, and managing ecosystems in a changing world. There's so much cool stuff to learn!

This indicates to me that Ewan has a good understanding of how things sort out in regard to what emerges from what: Molecular scalesEven with a complete parts list of proteins in humans, we are still clueless about what vast tracts of well-characterised protein coding genes actually do. For about 8000 proteins we have a good idea of at least one of their roles; for another around 7000 proteins we have some hints. But even this knowledge can be very partial. For example, the Huntingtin gene we know is involved in Huntington's disease via a trinucleotide expansion – yet we have almost no knowledge of its molecular function. We know other genes are key mediators in disease, for example C9orf72 in amyotrophic lateral sclerosis (of ice bucket fame), yet we know very little about about its cellular or molecular function. And this patchy knowledge gets far worse as we move away from proteins. Every year it feels like a new class of non-coding RNA is defined, but pinning down functions for them (including potentially no function, the hardest thing to show) is elusive, beyond some individual cases.

Cellular scalesImagine we knew the full parts list of proteins and RNAs, and their individual functions. Somehow these proteins go on to make cells, and the cells form organs. Huge unknowns dominate the landscape of cellular structure and mechanism. For example, the massive, Death-Star-like Vault complex has a large RNA component, hangs around in the nucleus and is quite easy to visualise with electron microscopy - but we have no firm idea of what it is doing. Or take the host of vesicles and membrane-bound structures zipping around every cell. Presumably they’re doing some kind of cellular ‘housekeeping’ (specific to different cell types), but we’re gloriously ignorant of the details. How do they know where they’re going? How does the right thing get into the right vesicle? As soon as you start poking into even the easiest-to-observe cellular phenomena, there are a surprising number of unknown components and their interactions.

Organ scalesResearch into nearly every combination of cells turns up far more questions than answers. Even ‘simple’ multi-cellular systems, like the gut, have mysterious ways of ensuring that the right cells divide and differentiate at the right time. In more complex systems, interactions between cells give rise to clearly observable (sometimes model-able) phenomena, for example beating heart muscle, or the capture and excretion of toxins.

I don't so mind when people funded from the NSF (or local equivalent) go on about the supposed purity of "basic science" (even if I think they should go read some Francis Bacon and learn that the distinction between basic and applied is a modern myth), but when it gets ridiculous is when people funded by the NIH (or again, local version) do the same. Seriously, if you don't care about helping people's health, why are you expecting an agency dedicated to exactly that to fund you?

Laurence A. Moran

Larry Moran is a Professor in the Department of Biochemistry at the University of Toronto. You can contact him by looking up his email address on the University of Toronto website.

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Quotations

The old argument of design in nature, as given by Paley, which formerly seemed to me to be so conclusive, fails, now that the law of natural selection has been discovered. We can no longer argue that, for instance, the beautiful hinge of a bivalve shell must have been made by an intelligent being, like the hinge of a door by man. There seems to be no more design in the variability of organic beings and in the action of natural selection, than in the course which the wind blows.Charles Darwin (c1880)Although I am fully convinced of the truth of the views given in this volume, I by no means expect to convince experienced naturalists whose minds are stocked with a multitude of facts all viewed, during a long course of years, from a point of view directly opposite to mine. It is so easy to hide our ignorance under such expressions as "plan of creation," "unity of design," etc., and to think that we give an explanation when we only restate a fact. Any one whose disposition leads him to attach more weight to unexplained difficulties than to the explanation of a certain number of facts will certainly reject the theory.

Charles Darwin (1859)Science reveals where religion conceals. Where religion purports to explain, it actually resorts to tautology. To assert that "God did it" is no more than an admission of ignorance dressed deceitfully as an explanation...

Quotations

The world is not inhabited exclusively by fools, and when a subject arouses intense interest, as this one has, something other than semantics is usually at stake.
Stephen Jay Gould (1982)
I have championed contingency, and will continue to do so, because its large realm and legitimate claims have been so poorly attended by evolutionary scientists who cannot discern the beat of this different drummer while their brains and ears remain tuned to only the sounds of general theory.
Stephen Jay Gould (2002) p.1339
The essence of Darwinism lies in its claim that natural selection creates the fit. Variation is ubiquitous and random in direction. It supplies raw material only. Natural selection directs the course of evolutionary change.
Stephen Jay Gould (1977)
Rudyard Kipling asked how the leopard got its spots, the rhino its wrinkled skin. He called his answers "just-so stories." When evolutionists try to explain form and behavior, they also tell just-so stories—and the agent is natural selection. Virtuosity in invention replaces testability as the criterion for acceptance.
Stephen Jay Gould (1980)
Since 'change of gene frequencies in populations' is the 'official' definition of evolution, randomness has transgressed Darwin's border and asserted itself as an agent of evolutionary change.
Stephen Jay Gould (1983) p.335
The first commandment for all versions of NOMA might be summarized by stating: "Thou shalt not mix the magisteria by claiming that God directly ordains important events in the history of nature by special interference knowable only through revelation and not accessible to science." In common parlance, we refer to such special interference as "miracle"—operationally defined as a unique and temporary suspension of natural law to reorder the facts of nature by divine fiat.
Stephen Jay Gould (1999) p.84

Quotations

My own view is that conclusions about the evolution of human behavior should be based on research at least as rigorous as that used in studying nonhuman animals. And if you read the animal behavior journals, you'll see that this requirement sets the bar pretty high, so that many assertions about evolutionary psychology sink without a trace.

Jerry Coyne
Why Evolution Is TrueI once made the remark that two things disappeared in 1990: one was communism, the other was biochemistry and that only one of them should be allowed to come back.

Sydney Brenner
TIBS Dec. 2000
It is naïve to think that if a species' environment changes the species must adapt or else become extinct.... Just as a changed environment need not set in motion selection for new adaptations, new adaptations may evolve in an unchanging environment if new mutations arise that are superior to any pre-existing variations

Douglas Futuyma
One of the most frightening things in the Western world, and in this country in particular, is the number of people who believe in things that are scientifically false. If someone tells me that the earth is less than 10,000 years old, in my opinion he should see a psychiatrist.

Francis Crick
There will be no difficulty in computers being adapted to biology. There will be luddites. But they will be buried.

Sydney Brenner
An atheist before Darwin could have said, following Hume: 'I have no explanation for complex biological design. All I know is that God isn't a good explanation, so we must wait and hope that somebody comes up with a better one.' I can't help feeling that such a position, though logically sound, would have left one feeling pretty unsatisfied, and that although atheism might have been logically tenable before Darwin, Darwin made it possible to be an intellectually fulfilled atheist

Richard Dawkins
Another curious aspect of the theory of evolution is that everybody thinks he understand it. I mean philosophers, social scientists, and so on. While in fact very few people understand it, actually as it stands, even as it stood when Darwin expressed it, and even less as we now may be able to understand it in biology.

Jacques Monod
The false view of evolution as a process of global optimizing has been applied literally by engineers who, taken in by a mistaken metaphor, have attempted to find globally optimal solutions to design problems by writing programs that model evolution by natural selection.